Natural killer cell cytotoxicity against intracellular bacteria

自然杀伤细胞对细胞内细菌的细胞毒性

基本信息

批准号：
10168917
负责人：
Edward A Miao
金额：
$ 5.3万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10168917
关键词：
Apoptosis Apoptotic Automobile Driving Bacteria Bacterial Infections Bacteriophages Biological Response Modifiers CASP1 gene CASP3 gene CASP7 gene CD94 Antigen Cancerous Caspase Categories Cell physiology Cells Chromobacterium Cleaved cell Cytolysis Data Detection Grant Granzyme Hepatocyte Immune Infection Infectious Agent Inflammasome Innate Immune System Interleukin-18 Knowledge Lead Listeria monocytogenes Malignant Neoplasms Mediating Modeling Mus Natural Killer Cell toxicity Natural Killer Cells Occupations Phase Poxviridae Predisposition Proteins Resistance Role Safety Series Specificity Therapeutic Therapeutic Intervention Viral Virus Work bactericide cell killing cell type combat cytokine cytokine release syndrome cytotoxic cytotoxicity fight against improved in vivo macrophage neutrophil pathogen perforin pressure prevent response therapeutic cytokines tool

项目摘要

ABSTRACT Natural killer cells are cytotoxic against virally infected cells and cancerous cells, but had never been shown to kill host cells harboring intracellular bacteria in vivo. We discovered the first two examples of this basic function of NK cells, which can kill hepatocytes infected by Listeria monocytogenes or Chromobacterium violaceum. This activity required exogenous or endogenous IL-18, respectively. This discovery originated from our search for bacteria that would fail to evade caspase-1 detection in vivo. A series of logical steps led us to discover that C. violaceum is extremely lethal to caspase-1 deficient mice, which succumb to as few as 100 CFUs. In stark contrast, WT mice are fully resistant, surviving 1,000,000 CFU systemic challenge. This new model led us to make a surprising new discovery. Approximately half of the caspase-1 directed defense was via IL-18, which stimulates NK cells to kill C. violaceum infected hepatocytes via perforin mediated cytotoxicity. Vertebrate adapted pathogens have strong selective pressure to evade inflammasomes – we have previously show this is the case for L. monocytogenes. This led us to postulate that L. monocytogenes evades NK cells by preventing IL-18 secretion, and indeed, when we treated mice with therapeutic IL-18, the NK cytotoxic response is restored. In this grant we explore how NK cytotoxicity drives the clearance of L. monocytogenes and C. violaceum. We study the role of NKG2D in identifying infected cells, explore the proteins that are targeted by granzymes in the target infected hepatocytes, and study the fate of infected hepatocytes after they are killed.

抽象的天然杀伤细胞针对几乎受感染的细胞和取消细胞具有细胞毒性，但从未有过证明可以杀死体内含有细胞内细菌的宿主细胞。我们发现了前两个例子 NK细胞的基本功能，该功能可以杀死由单核细胞增生李斯特菌感染或染色体感染的肝细胞紫罗兰。该活动分别需要外源性或内源性IL-18。这一发现源自我们寻找的细菌，这些细菌无法逃避caspase-1检测体内。一系列逻辑步骤使我们发现，紫c。小鼠，屈服于只有100个CFU的小鼠。与之形成鲜明对比，WT小鼠完全抗性，存活 1,000,000 CFU系统性挑战。这个新模型使我们做出了令人惊讶的新发现。大约 caspase-1的一半定向防御是通过IL-18，它刺激了NK细胞杀死被感染的紫c。肝细胞通过穿孔蛋白介导的细胞毒性。脊椎动物适应的病原体具有强大的选择压力逃避炎症 - 我们以前证明了单核细胞增生李斯特菌的情况。这导致了我们假设单核细胞增生李斯特氏菌通过预防IL-18分泌来逃避NK细胞，实际上，当我们处理具有治疗性IL-18的小鼠，恢复了NK细胞毒性反应。在这笔赠款中，我们探讨了NK细胞毒性如何驱动单核细胞增生李斯特氏菌和C的清除率。紫罗兰。我们研究了NKG2D在识别受感染细胞中的作用，探索由靶标的颗粒状感染了肝细胞，并研究了被杀死后感染的肝细胞的命运。